DESCRIPTION: Oxidative free-radical cyclizations, in which the initial radical is generated oxidatively, and/or the cyclic radical is oxidized to terminate the reaction, have considerable synthetic potential since more highly functionalized products can be prepared from simpler precursors than with the standard tin hydride reductive radical cyclizations. The goal of this research is to develop oxidative free- radical cyclization into a reliable and versatile method for the synthesis of highly functionalized cyclic and polycyclic compounds. The PI's studies over the past ten years have shown that this will be a valuable synthetic method for formation of radicals from 1,3-dicarbonyl compounds and related acidic substrates. The PI has recently discovered that high yields of cyclic products can be obtained from monocarbonyl compounds at minus 80 oC under some circumstances. Preliminary results suggest that high yields are obtained from ketones in which enolization is possible or favored to only one side of the ketone and when the product can't enolize thereby preventing further oxidation of the product. Oxidative cyclizations of a conjugated enone and an aldehyde containing an unsaturated side chain also proceed in good yield. The PI wishes to fully explore and develop the scope of these reactions. Since these starting materials are very simple, the oxidative cyclization of monocarbonyl compounds should have even broader scope and utility in synthesis than those of 1,3-dicarbonyl compounds. The focus of the oxidative free radical cyclization project is the development of new synthetic methodology that will be broadly applicable in the synthesis of wide variety of biologically active compounds. The PI plans to use oxidative free-radical cyclizations for short syntheses of gymnomitrol and upial. In both cases the syntheses are designed to demonstrate the potential utility of this reaction by the simple synthesis of a moderately complex natural product. The gymnomitrol synthesis requires only three steps from a previously prepared intermediate. The upial synthesis utilizes oxidative cyclization to convert a readily available cyclohexane-1,3-dione to a complex bicyclic dione. The antibiotic diterpenes cyathin B3, allocyathin B2 and the nerve growth factor production stimulant erinacine A will be prepared by efficient, stereospecific syntheses using a Lewis acid catalyzed ene reaction to give a tricyclic dienol containing the complete carbon skeleton, proper stereochemistry and suitable functionality for completion of the syntheses. The structurally novel, potent hepatotoxin cylindrospermopsin will be synthesized by the addition of ammonia to a dienone, condensation of the resulting diamine with a thiourea derivative, and epoxide opening to construct the ticyclic guanidinium core of cylindrospermopsin with control of all but one of the 6 stereo centers.